These studies were designed to examine various aspects of the regulation of cholesterol synthesis in different tissues of the body. The first group of investigations explore the role of activation of the rate limiting enzyme in the cholesterol biosynthetic pathway on the regulation of overall synthesis in different tissues. The ratio of active to inactive forms of this enzyme will be measured in animals subjected to various physiological manipulations. In a second group of studies the ratio of hydrogen to carbon incorporation into the sterol nucleus will be measured in different tissues. This ratio will then be utilized to quantitate rates of cholesterol synthesis in various tissues in experimental animals under in vivo conditions. Such data should give quantitative information on the relative importance of different organ systems as biosynthetic sites for cholesterol. In a third set of studies the transport mechanism in the liver cell responsible for uptake of chylomicron remnant cholesterol will be further characterized by measuring the kinetics of the transport process in the isolated perfused liver and by use of both scanning and transmission electronmicroscopy. In a fourth set of studies the saturable transport system responsible for the uptake of cholesterol carried in high density lipoproteins in the endocrine organs will be further characterized. It will be determined whether this transport mechanism is separate from similar mechanisms responsible for the uptake of low density lipoprotein cholesterol and the role of this degradative pathway in the turnover of high density lipoprotein cholesterol will be examined. Finally, utilizing the perfused liver, the contribution of synthesis and dietary and lipoprotein cholesterol to the metabolically active pools of sterol in the liver cell will be explored. Taken together, these studies will provide important new information on the regulatory mechanisms operative in controlling cholesterol metabolism in animals and in man and should provide insights into the causes of hypercholesterolemia.